As a group of heterogeneous diseases the osteochondrodysplasias have a complex aetiology, but are likely to share similar bask mechanisms of disease initiation, progression and end-stage pathology. In this context the principle objective of the proposed work is to determine the molecular, cell and extracellular matrix pathology of three distinct chondrodysplasia phenotypes, which result from mutations in the C-terminal globular domains of two different structural proteins that are important for normal bone development. From this approach we can expect to identify common basic mechanisms and learn general principles about genotype-phenotype correlations in other chondrodysplasia phenotypes. These data will ultimately help in developing therapeutic strategies that might be targeted to a range of individual phenotypes. Specifically, we will generate knock-in mouse models of (i) pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) resulting from mutations in the C-terminal globular domain of cartilage oligomeric matrix protein (COMP), and (ii) metaphyseal chondrodysplasia type Schmid (MCDS) resulting from a mutation in the C-terminal globular domain of type X Collagen. We will use these targeted mouse models to determine in vivo the disease pathology by using immuno-histochemistry, transmission electron microscopy, in situ hybridisation and proteornics to study in-depth the affected tissues to understand the pathological sequence of events and secondary mechanisms of pathogenesis. Furthermore, we will use cells and tissues from these mice to develop in vitro approaches for studying the disease processes, thereby fully exploiting the targeted mouse models as we establish, test and compare in vivo/in vitro correlations.